More than one-third of all cases of dilated cardiomyopathy are caused by inherited mutations, with 5% to 10% of these mutations being linked to the LMNA gene, which encodes the nuclear envelope proteins lamin A and C. Importantly, mutations in the LMNA gene are also responsible for a broad spectrum of other diseases, including Emery-Dreifuss muscular dystrophy, limb-girdle muscular dystrophy and familial partial lipodystrophy. Despite recent advances, the mechanism(s) responsible for the often muscle-specific defects caused by different lamin mutations remains elusive. The central hypothesis of this proposal is that lamin mutations can cause skeletal and cardiac muscle disease through two, possibly overlapping mechanisms: (i) loss of structural function of lamins A and C, leading to rupture of the more fragile nucleus in mechanically stressed tissues; (ii) disturbing (mechanosensitive) signaling pathways that results in impaired function of muscle cells. Specific LMNA mutations may differentially affect these distinct aspects of lamin function, resulting in a broad spectrum of disease phenotypes. My long term goal is to understand the molecular mechanism(s) by which mutations in the nearly ubiquitously expressed lamins can lead to muscle-specific phenotypes and to explore to what extent impaired nuclear structure and altered cellular sensitivity to mechanical stress contribute to the muscle-specific phenotypes. In the first aim, we will test the hypothesis that altered nuclear mechanics result in increased nuclear rupture in mechanically stressed tissue. By using a genetic reporter assay that can detect even transiently compromised nuclear envelope integrity in cardiac myocytes in three mouse models of muscular laminopathies, we can directly assess whether mutations in nuclear envelope proteins cause increased rates of nuclear rupture in cardiac tissue. In the second aim, we will determine the relationship between impaired nuclear mechanics and the severity of muscular phenotypes in laminopathies. Using drosophila melanogaster models expressing a panel of lamin mutations with variable muscle involvement, we will relate effects of the mutations on the mechanical properties of nuclei in intact muscle tissue in drosophila larvae with the severity of muscle defects in adult flies. In the third aim, we will investigate the interplay between lamin mutations responsible for dilated cardiomyopathy and a specific signaling pathway, myocardin-related transcription factor A (MRTF-A). We will explore the mechanism(s) responsible for the impaired nuclear translocation of MRTF-A in lamin A/C-deficient and mutant cells we recently discovered and assess the functional consequences of impaired MRTF-A signaling on cellular function. Studying the effects of lamin mutations on nuclear structure and cellular signaling will improve our understanding of normal and tissue-specific functions of these proteins and lead to new insights into the molecular mechanisms responsible for dilated cardiomyopathy, Emery-Dreifuss muscular dystrophy and other laminopathies, potentially providing new targets for the treatment of these diseases.
Heart disease and muscular dystrophies, characterized by progressive wasting of muscles in the arms, legs, and trunk of patients, are often caused by inherited mutations in specific genes. Our studies will address the disease mechanism by which mutations in a particular gene cause these muscle-specific defects and may also lead to new insights into the normal function of the proteins encoded by the mutated gene. A better understanding of how these mutations can alter the structure and function of muscle cells and impair critical signaling pathways could open the door for pharmacological approaches to normalize these pathways, potentially leading to new clinical treatments for patients affected by these diseases.
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